Nature. 2010 Jun 17;465(7300):885-90. Epub 2010 May 19.

Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling.External

Lin, S. C., Lo, Y. C., Wu, H.,
--- - Department of Biochemistry, Weill Cornell Medical College, New York, New York 10021, USA.
MyD88, IRAK4 and IRAK2 are critical signalling mediators of the TLR/IL1-R superfamily. Here we report the crystal structure of the MyD88-IRAK4-IRAK2 death domain (DD) complex, which surprisingly reveals a left-handed helical oligomer that consists of 6 MyD88, 4 IRAK4 and 4 IRAK2 DDs. Assembly of this helical signalling tower is hierarchical, in which MyD88 recruits IRAK4 and the MyD88-IRAK4 complex recruits the IRAK4 substrates IRAK2 or the related IRAK1. Formation of these Myddosome complexes brings the kinase domains of IRAKs into proximity for phosphorylation and activation. Composite binding sites are required for recruitment of the individual DDs in the complex, which are confirmed by mutagenesis and previously identified signalling mutations. Specificities in Myddosome formation are dictated by both molecular complementarity and correspondence of surface electrostatics. The MyD88-IRAK4-IRAK2 complex provides a template for Toll signalling in Drosophila and an elegant mechanism for versatile assembly and regulation of DD complexes in signal transduction.
PMID: 20485341External
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
In vivo interaction
  Endogenous
expression
Overexpression DD1 DD2 Reference
Family DD1 DD2 Method Species Region Species Region
DD IRAK2 Link IRAK4 His fusion protein pull-down E.coli Human 1-112 Human 4-106 20485341
DD IRAK2 Link Myd88 His fusion protein pull-down E.coli Human 1-112 Human 20-117 20485341
DD IRAK4 Link Myd88 His fusion protein pull-down E.coli Human 4-106 Human 20-117 20485341
(Link: click this icon to show interactions only between the two corresponding DDs)
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
Characterization
  Stoichiometry Affinity Protein-Protein interface Reference
Family DD1 DD2 Method Mutation Complex structure
DD IRAK2 Link IRAK4 Structure 6:4:4 Y6D, W62D, M66D, R67D (IRAK2) 3MOP 20485341
DD IRAK2 Link Myd88 Structure 6:4:4 3MOP 20485341
DD IRAK4 Link Myd88 Structure 6:4:4 N16E and R20E, E69K, T76E, N78E, R12A (IRAK4) V43D, E52K, I61A, Y58A and R62A, R62E, A44E (Myd88) 3MOP 20485341
(Link: click this icon to show interactions only between the two corresponding DDs)